p21-activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor.
GEF-H1 is a guanine nucleotide exchange factor for Rho whose activity is regulated through a cycle of microtubule binding and release. Here we identify a region in the carboxyl terminus of GEF-H1 that is important for suppression of its guanine nucleotide exchange activity by microtubules. This portion of the protein ... includes a coiled-coil motif, a proline-rich motif that may interact with Src homology 3 domain-containing proteins, and a potential binding site for 14-3-3 proteins. We identify GEF-H1 as a binding target and substrate for p21-activated kinase 1 (PAK1), an effector of Rac and Cdc42 GTPases, using an affinity-based screen and localize a PAK1 phosphorylation site to the inhibitory carboxyl-terminal region of GEF-H1. We show that phosphorylation of GEF-H1 at Ser(885) by PAK1 induces 14-3-3 binding to the exchange factor and relocation of 14-3-3 to microtubules. Phosphorylation of GEF-H1 by PAK may be involved in regulation of GEF-H1 activity and may serve to coordinate Rho-, Rac-, and Cdc42-mediated signaling pathways.
Mesh Terms:
14-3-3 Proteins, Animals, Binding Sites, Guanine Nucleotide Exchange Factors, Hela Cells, Humans, Jurkat Cells, Microtubule Proteins, Microtubules, Phosphorylation, Protein Interaction Mapping, Protein Transport, Protein-Serine-Threonine Kinases, Transfection, Tyrosine 3-Monooxygenase, p21-Activated Kinases
14-3-3 Proteins, Animals, Binding Sites, Guanine Nucleotide Exchange Factors, Hela Cells, Humans, Jurkat Cells, Microtubule Proteins, Microtubules, Phosphorylation, Protein Interaction Mapping, Protein Transport, Protein-Serine-Threonine Kinases, Transfection, Tyrosine 3-Monooxygenase, p21-Activated Kinases
J. Biol. Chem.
Date: Apr. 30, 2004
PubMed ID: 14970201
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